Antihypertensive effect of the combination of fosinopril and HCTZ is resistant to interference by nonsteroidal antiinflammatory drugs.

Nonsteroidal antiinflammatory drugs (NSAID) are frequently reported to interfere with the blood pressure lowering actions of various antihypertensive medications. We studied 17 women with arthritis and hypertension who were receiving fosinopril and HCTZ, and administered sequentially in random order ibuprofen, sulindac, and nabumetone for 1 month each, with an intervening 2-week washout period between each treatment period. During the washout period, subjects received acetaminophen. Blood pressure at the end of 2 weeks of acetaminophen was compared with blood pressure after 1 month of treatment with each of the NSAID. Mean blood pressure was unchanged before and after all NSAID: 108 +/- 7 v 107 +/- 9 for nabumetone, 108 +/-9 v 108 +/- 9 for sulindac, and 108 +/- 8 v 107 +/- 9 for ibuprofen. The 24-h urinary sodium excretion was not significantly different. We conclude that the three NSAID did not neutralize the antihypertensive effect of the combination of fosinopril and HCTZ, and hence the blood pressure lowering action of the combination may not be prostaglandin dependent.

End-stage renal disease in specific ethnic and racial groups: risk factors and benefits of antihypertensive therapy.

During the past few years, it has become apparent that there are factors that place a person at greater risk for the development and progression of renal failure. This has been documented since the early 1980s by the United States Renal Data System that has collected data confirming that end-stage renal disease occurs at a greater rate in certain subpopulations of Americans. It is evident from an examination of the data that African Americans and American Indians have an incidence of end-stage renal disease that is not proportional to their percentage of the total population. In fact, African Americans and American Indians are reported to have at least a 4-fold greater incidence of end-stage renal disease than white Americans. There have been 5 factors identified: hypertension, glucose intolerance, insulin resistance, salt sensitivity, and hyperlipidemia, which may play a greater role in these subpopulations. In addition, as with other populations, lifestyle issues may serve to alter these primary risk factors or may act as direct modulators of renal disease progression. There is also a possibility that interactions between risk factors frequently occur that may modify the development or progression of the disease. This article reviews these risk factors and emphasizes the interaction between hypertension and the other factors. In addition, the effects of antihypertensive agents on risk factors and on renal outcome are emphasized. Where possible, issues specific to African Americans and American Indians are underscored; however, one must accept that the database on these populations is only now developing. This review should help the clinician make appropriate choices when prescribing antihypertensive therapy for patients who may be at risk of developing progressive renal failure.

Parenteral hydralazine revisited.

Historical aspects of the development and application of the vasodilator hydralazine are reviewed. The pharmacology, pharmacokinetics, metabolism, and mechanism of action are discussed, with emphasis on the parenteral use of this drug. It is reiterated that parenteral hydralazine is the preferred drug for the treatment of severe preeclampsia, but its usefulness in other forms of accelerated hypertension is also addressed. Through comparisons with other established antihypertensive agents, the efficacy and pharmacoeconomic potential of hydralazine are stressed.

Comparative effects of nabumetone, sulindac, and ibuprofen on renal function.

OBJECTIVE: Nonsteroidal antiinflammatory drugs (NSAID) have been associated with hemodynamically mediated acute renal failure. There appear to be differences among NSAID in producing this effect. We compare renal effects of ibuprofen, sulindac, and nabumetone. METHODS: Seventeen women over age 56 receiving hydrochlorothiazide and fosinopril for hypertension who had osteoarthritis requiring NSAID received 3 different NSAID to evaluate potential varying renal effects. In an investigator blinded randomized study, patients received nabumetone, sulindac, or ibuprofen for 1 month with intervening 2 week control periods. After each period renal function was assessed by inulin and para-aminohippurate clearances and urinary prostaglandins were measured. RESULTS: No overall statistical differences among the NSAID were observed. However, there were clinically meaningful differences during ibuprofen therapy: 4 patients developed a clinically significant decrease in renal function; during sulindac therapy one of these also developed a clinically significant decrease in renal function. During nabumetone there were 0 episodes of clinically significant decrease in renal function. Using Gomez equations, glomerular hydrostatic pressure and afferent and efferent arteriolar resistances were estimated. None changed overall during any intervention. However, the 4 patients who developed decreased renal function while taking ibuprofen were analyzed separately. Glomerular hydrostatic pressure decreased 15%; afferent arteriolar resistance increased 85%. These changes were associated with marked decreases in vasodilatory prostaglandins compared to patients receiving ibuprofen who did not develop decreases in renal function. CONCLUSION: There are differences in effect on renal function among NSAID. These can be correlated with specific alterations in suppression of the cyclooxygenase system cascade and related to changes in the hemodynamic control of glomerular filtration.

Calcium antagonists and the kidney.

Calcium antagonists have evolved as an important class of cardiovascular therapeutic agents. Usefulness in treating hypertension, angina pectoris, and cardiac arrhythmias has been established. Investigations show that calcium antagonists have a role in altering renal functions. They are natriuretic and may benefit salt-sensitive hypertensives. They have been shown to block vasoconstriction of the afferent arteriole in the presence of constrictors such as endothelin, thromboxane, norepinephrine, and angiotensin II. These vasoconstrictors may be mediators of nephrotoxins such as radiocontrast agents, and cyclosporine A. Actions of calcium antagonists which are being investigated for potential benefit in ameliorating chronic renal disease include: preventing glomerular hypertrophy, blocking angiotensin II-mediated macromolecule entry into mesangial cells and cytokine release, free-radical scavenger activity, and decreasing calcium deposition within the kidney. Slowing the progression of renal disease with the calcium antagonists has been demonstrated in both short- and long-term trials. Further studies are currently underway.

Labetalol and other agents that block both alpha- and beta-adrenergic receptors.

BACKGROUND: Labetalol, a compound that blocks both alpha- and beta-adrenergic receptors, is the only drug of its class currently available in the United States. OBJECTIVE: To review the pharmacology of labetalol and related compounds. SUMMARY: Unlike "pure" beta blockers, labetalol maintains cardiac output, reduces total peripheral resistance, and does not decrease peripheral blood flow. It has been used to treat hypertension of all degrees of severity and may be especially useful in black patients, elderly patients, patients with renal disease, and in pregnancy. It can be used in conditions that produce catecholamine crises, such as pheochromocytoma, clonidine withdrawal, and cocaine overdose. Its hemodynamic profile is attractive for use in myocardial ischemia. The parenteral form is useful in situations where blood pressure must be lowered quickly. The major side effect is orthostatic hypotension, and hepatotoxicity has been reported. CONCLUSIONS: Labetalol has several advantages over pure beta-blocking drugs and offers an alternative in managing hypertension that is difficult to control.

Renal failure and hyperkalemia associated with ketorolac tromethamine.

Three patients who were treated with ketorolac tromethamine (Toradol), an injectable nonsteroidal anti-inflammatory drug for pain management, developed acute renal failure or hyperkalemia or both. These complications were reversible in two cases after discontinuing the drug. Clinical conditions preexisted in each patient that rendered them susceptible to the renal complications of nonsteroidal anti-inflammatory use. It is well known that caution should be observed while using nonsteroidal anti-inflammatory drugs in patients whose renal function may be preserved through prostaglandin-mediated vasodilatory effects. The same cautions apply to ketorolac. Since its major marketed use is as an analgesic and its potent effect on prostaglandin synthesis may not be well recognized, those cautions must be emphasized.

Transdermal clonidine as an adjunct to enalapril: an evaluation of efficacy and patient compliance.

This four-center, 20-week, open-label study evaluated transdermal clonidine as an adjunct to enalapril 10 mg daily and demonstrated patterns of compliance. Seventy-four mildly to moderately hypertensive patients (mean seated blood pressure, 150/101 mm Hg) received enalapril 10 mg once daily as initial monotherapy. In 66 patients, the seated diastolic blood pressure remained greater than or equal to 90 mm Hg at the trough blood levels of enalapril. Transdermal clonidine (3.5 cm2, 7.0 cm2, or 10.5 cm2, equivalent to 0.1 mg, 0.2 mg, and 0.3 mg clonidine/day, respectively) then was added as needed to achieve blood pressure control. Forty-eight patients achieved diastolic blood pressures less than 90 mm Hg on concomitant therapy; 44 patients completed 8 weeks of maintenance dosing with a mean blood pressure of 134/85 mm Hg. Oral compliance, as measured by an electronic device that was actuated each time the medication vial was opened, varied from 48 to 140%. Compliance with the transdermal clonidine regimen was excellent; the patch was worn as directed during 96% of the patient-weeks of therapy. The authors conclude that blood pressure can be controlled by a combination of transdermal clonidine and enalapril in patients that do not adequately respond to enalapril monotherapy. Patients poorly complying with oral regimens may be candidates for a trial of transdermal clonidine monotherapy.

Therapeutic adherence in the elderly: transdermal clonidine compared to oral verapamil for hypertension.

This double-blind, double-dummy, randomized clinical trial, conducted in elderly patients with mild hypertension, compared adherence to treatment, efficacy, side effects, and quality of life during treatment with transdermal clonidine versus oral sustained-release verapamil (verapamil-SR). Blood pressure declined significantly--from 148/95 mm Hg at baseline to 139/84 after titration and 135/86 after maintenance--with transdermal clonidine (n = 29), and from 156/96 to 144/85 and 148/88, respectively, with verapamil-SR (n = 29). Adverse event rates and quality-of-life questionnaire responses were similar in the two treatment groups. Transdermal clonidine was worn as directed during more than 96% of patient-weeks of treatment. Compliance with the oral verapamil regimen was less consistent: Verapamil-SR was taken as directed during approximately 50% of patient-weeks of therapy, and individual compliance, assessed by tablet counts, varied from 50-120%. In all, 86% of subjects were satisfied or highly satisfied with the convenience of transdermal therapy; 87% reported that side effects were slightly or not bothersome; 65% indicated that transdermal patches were more convenient than oral therapy; and almost 60% preferred transdermal to oral therapy. In this study transdermal clonidine and oral verapamil were equally safe and effective. A substantial majority of patients preferred transdermal to oral therapy, and adherence to treatment was greater with transdermal therapy.

Intravenous nicardipine: an effective new agent for the treatment of severe hypertension.

Fifty-six patients with severe hypertension were treated with intravenous nicardipine for infusion periods of eight to twenty-four hours. Each patient achieved satisfactory blood pressure control during the infusion period with a mean controlling dose of 7.85 mg/hr. The dose of nicardipine needed for sustained blood pressure control correlated with untreated diastolic blood pressure but not with untreated systolic blood pressure. These results demonstrate the potential usefulness of intravenous nicardipine for the treatment of severe hypertension requiring rapid lowering, and they suggest also that the severity of pretreatment diastolic hypertension might be a useful indicator of the dose required for blood pressure control.

Intravenous nicardipine hydrochloride: treatment of patients with severe hypertension.

Nicardipine hydrochloride, a dihydropyridine calcium entry-blocking drug, was administered to 66 patients with severe hypertension during three protocols designed to examine the efficacy and safety of this investigation drug. It was shown that nicardipine was uniformly effective in lowering blood pressure to a therapeutic goal of 95 mm Hg. Time to achieve therapeutic effect was dose dependent, and steady-state blood levels were achieved after 8 to 12 hours. Reductions in both systolic and diastolic blood pressure but not changes in heart rate were correlated with plasma concentrations of nicardipine. In dose-ranging studies, the minimal effective dose of nicardipine appeared to be 2 mg/hr; 1 mg/hr was an ineffective dose, and little additional effect was seen above 4 mg/hr. Side effects were modest and consisted of those associated with vasodilation--headache, flushing, and feelings of warmth. In the initial group of patients studied, local thrombophlebitis occurred in a substantial number of patients. This was seen only after 14 hours of infusion. In subsequent studies, the infusion site was changed after 12 hours, and no further cases of thrombophlebitis were seen. Nicardipine appears to be therapeutic agent for parenteral use that shows promise in the treatment of severe hypertension.

Nicardipine in severe hypertension: oral therapy following intravenous treatment.

Nicardipine is an investigational dihydropyridine calcium-channel blocker. In the present study, 21 patients with severe hypertension were treated with oral nicardipine, alone or in combination with beta-blockers and diuretics for 4-5 weeks, following initial control of their blood pressure with intravenous nicardipine. Each of the 21 patients had a satisfactory response to intravenous nicardipine which was administered as an infusion following initial blood pressure lowering. At 1 h prior to discontinuation of the intravenous treatment, oral nicardipine therapy was begun as a 40 mg dose. Oral nicardipine, 40 mg t.i.d., was continued for the remainder of hospitalization and for a 4-5-week outpatient follow-up period. The dose of oral nicardipine was downtitrated and additional antihypertensive drugs, beta-adrenergic blocking agents and/or diuretics, were added to maintain blood pressure in an acceptable range. Compared to baseline, mean supine systolic blood pressure was lowered significantly (p less than 0.001) by 57 mmHg at the end of intravenous maintenance and by 50 mmHg at the end of oral treatment. Likewise, significant (p less than 0.001) decreases in diastolic blood pressure of 43 and 32 mmHg, respectively, were observed for the same time periods. At the end of oral treatment, 6 patients remained on nicardipine monotherapy, 8 patients were on two-drug therapy and 7 patients required three-drug therapy. Side-effects were mild except for a moderate headache reported in one patient during intravenous treatment. From these observations we conclude that oral nicardipine is a useful new agent for initial, single treatment of chronic severe hypertension, although a significant number of patients eventually need additional antihypertensive therapy.

Ureteral obstruction due to blood clot following percutaneous renal biopsy: resolution with intraureteral streptokinase.

The nonsurgical approach to unilateral ureteral obstruction due to impaction of a blood clot is described. A patient with the nephrotic syndrome secondary to minimal change disease had gross hematuria and acute renal failure following percutaneous renal biopsy. After he responded to prednisone therapy, clot obstruction developed at the site of the percutaneous biopsied kidney, which was treated with intracaliceal infusion of streptokinase via a ureteral catheter. Complete resolution of the clot and the urinary tract obstruction was accomplished within 3 days. This approach appears to be the treatment of choice in upper urinary tract obstruction secondary to blood clots when simple ureteral catheter drainage is ineffective.

The effects of mercuric chloride on calmodulin-mediated Ca2+ transport in rat brain.

We have shown previously that mercuric chloride (HgCl2) inhibits in vitro vasopressin release from the isolated rat neurohypophysis with maximum inhibition occurring with 0.5 mM HgCl2. Associated with the inhibition of hormone release is an increase in 45Ca+2 uptake, an increase in cytosolic 45Ca+2, and a reduction of 45Ca+2 accumulation by mitochondria in the intact gland. In the present series of studies, the effect of HgCl2 on calmodulin (CM) function in neural tissue preparations is reported. Mercuric chloride (0.5 mM) reduced 45Ca+2 binding to CM purified from bovine neurohypophyses by 20% and inhibited endogenous CM-stimulated Ca,Mg-ATPase activity from rat brain mitochondria in a dose-dependent fashion. Ca,Mg-ATPase activity was inhibited by 50 and 80% with 0.5 and 5.0 mM HgCl2, respectively. CM-stimulation of Ca,Mg-ATPase activity was inhibited by calmidazolium (CMZ) with maximal inhibition seen with 0.1 mM CMZ. Reversibility of the HgCl2 interaction with CM was demonstrated using CM-stimulated phosphodiesterase (PDEase) activity from rat brain. HgCl2 inhibited both basal and CM-stimulated PDEase activity in a dose-dependent manner with maximum inhibition occurring with 1.0 mM HgCl2. Preexposure of CM to an inhibitory concentration (1.0 mM) of HgCl2 resulted in no loss of stimulatory PDEase enzyme activity. From these results, we conclude that HgCl2 reversibly interferes with 45Ca+2 binding to CM and also inhibits CM-regulated Ca+2 pumping enzyme systems in the neurohypophysis. The inhibition of vasopressin release from the intact gland in the presence of HgCl2 thus, may be associated with a disruption of calcium in the neurohypophysis.

Changes of plasma renin activity and atrial natriuretic factor during intravenous nicardipine treatment of severe hypertension.

Intravenous nicardipine was given to 32 severe hypertensive patients in an increasing dose, titration fashion. Samples for plasma renin activity and plasma atrial natriuretic factor concentration were obtained at the following times: before treatment, at the time of titration response and at the end of a maintenance period. The mean time required to achieve the titration response was 29 min. Plasma renin activity was increased by 32% (p less than 0.05) at the titration response and 181% (p less than 0.005) at the end of an 8-12 h maintenance nicardipine infusion. Atrial natriuretic factor concentration was unchanged from baseline at titration response and was decreased by 25% (p less than 0.005) at the end of maintenance. Mean plasma nicardipine dose was 6.95 mg/h at the titration response and 8.76 mg/h at the end of maintenance. These results suggest that alterations in plasma renin activity and atrial natriuretic factor concentrations may be associated with blood pressure reduction rather than with a direct drug action on release mechanisms.

Dilevalol in severe hypertension. A multicenter trial of bolus intravenous dosing.

Dilevalol, the R-R optical isomer of labetalol, a nonselective beta-antagonist with vasodilation from selective beta 2 agonism, was administered in sequential multiple bolus intravenous injections of 10 to 100 mg in total doses ranging from 35 to 585 mg (mean dose, 414 mg) to 101 patients with supine diastolic blood pressures above 120 mm Hg. Mean blood pressure was reduced from 200 (+/- 3)/129 (+/- 1) mm Hg to 149 (+/- 2)/101 (+/- 1) mm Hg, a mean reduction of 51/28 mm Hg. The therapeutic goal was established as a reduction in supine diastolic blood pressure to less than 100 mm Hg or a reduction of at least 30 mm Hg. This was achieved in 62 (61%) of 101 patients, with an additional 7 patients having a final supine diastolic blood pressure of 100 mm Hg. Treatment with dilevalol was less successful in black male patients than in the group at large. There was a tendency for older patients to respond better than younger patients. Prior recent treatment of patients with beta-adrenergic antagonists decreased the effectiveness of the drug. Significant orthostatic hypotension was not noted. Sixty-four patients were transferred to oral dilevalol treatment in combination with a diuretic, and blood pressure in this group averaged 160/100 mm Hg after 1 month of therapy. Dilevalol appears to be a safe and effective drug that can be used intravenously successfully in the majority of patients with severe hypertension and provides an alternative to therapy with other agents. It also is a useful agent for oral treatment of these patients after successful intravenous therapy.

Intravenous nicardipine for the treatment of severe hypertension. A double-blind, placebo-controlled multicenter trial.

A placebo-controlled, double-blind multicenter trial was conducted in 123 patients with severe hypertension to examine the efficacy and safety of intravenously administered nicardipine hydrochloride in controlling blood pressure. Seventy-three patients were initially randomized to receive nicardipine treatment. This group had an initial blood pressure of 213 +/- 3/126 +/- 2 mm Hg. Sixty-seven patients achieved the therapeutic goal (diastolic blood pressure less than or equal to 95 mm Hg; systolic blood pressure less than or equal to 160 mm Hg). Fifty patients were randomized to receive placebo solution. Blood pressure in these patients was 216 +/- 3/125 +/- 2 mm Hg. No patient in this group achieved the therapeutic goal during the "blinded" portion of the study. Forty-four of 49 patients who did not respond to placebo administration responded to subsequent treatment with nicardipine. Patients with end-organ damage were included in the study. These included patients with left ventricular hypertrophy, retinopathy, and renal insufficiency. Patients with and without end-organ damage responded equally well to nicardipine treatment. Serious adverse experiences were infrequent, the most common adverse reaction being headache in 24% of the patients studied.

Dilevalol: a selective beta-2 adrenergic agonist vasodilator with beta adrenergic blocking activity.

Dilevalol is the R-R' optical isomer of labetalol and differs pharmacologically from the racemic mixture in the following ways: it is seven-fold more potent as a selective beta-2 agonist; it is four times more potent as a nonselective beta antagonist; it has no clinically significant alpha antagonist property. Dilevalol is a vasodilator and reduces blood pressure by reducing systemic vascular resistance. It has a half-life of 15-18 hours, and is demonstrated to be effective as an antihypertensive agent for 24-30 hours. Hemodynamic studies in humans show that following administration of dilevalol either orally or intravenously, blood pressure falls as a consequence of a decrease in systemic vascular resistance. Cardiac index is unchanged and heart rate decreases slightly. Dilevalol is shown to cause regression of left ventricular hypertrophy in younger individuals, to improve left ventricular performance and to have no effect on parameters of renal function. Prospective double-blinded clinical trials in comparison with placebo, propranolol, metoprolol and atenolol were conducted and demonstrate dilevalol to be an effective antihypertensive agent with a favorable side effect profile with a particularly low incidence of central nervous system side effects.

A multicenter double-blind study of the efficacy and safety of once and twice daily dilevalol compared to propranolol.

Dilevalol, the R,R isomer of labetalol, is a non-selective beta-adrenergic blocking drug with vasodilator properties which differ from those of labetalol in that they are attributable to beta-2 agonism rather than alpha-1 blockade. This multicenter, double-blind, randomized study compares the antihypertensive efficacy and safety of dilevalol with propranolol and, in addition, compares the efficacy of dilevalol when given once daily with twice daily. Caucasian patients with mild and moderate essential uncomplicated hypertension were divided into three treatment groups and received either propranolol twice daily (N = 59), dilevalol twice daily (N = 60), or dilevalol once daily (N = 53). Patients were given increasing doses of these medications over a 2 to 10 week period to achieve a supine diastolic blood pressure (SuDBP) of less than 90 mm Hg. The three regimens were equally effective in lowering supine blood pressure (dilevalol daily and twice daily reduced SuDBP by 14 Hg and propranolol by 13 mm Hg). Patients with at least a 5 mm Hg reduction in SuDBP then entered a two month maintenance phase. Dilevalol, whether given once (N = 40) or twice daily (N = 55) maintained the supine systolic blood pressure more effectively (dilevalol daily--15 mm Hg, twice daily--13 mm Hg, P less than .05) than propranolol (N = 53, 11 mm Hg) and dilevalol given once daily maintained diastolic blood pressure more effectively than propranolol (17 mm Hg v 14 mm Hg, P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Intravenous nicardipine in severe systemic hypertension.

Sixty-six patients with severe hypertension were treated with intravenous nicardipine in 3 separate protocols. Each protocol had a common end point: Diastolic blood pressure would either reduce 25 mm Hg or measure below 95 mm Hg. Each of the 66 patients studied attained the desired clinical response end point. Intravenous nicardipine produced a gradual reduction in blood pressure, was effective in maintaining blood pressure control during constant infusion and had few undesirable effects. These observations suggest that intravenous nicardipine maybe a useful addition to a limited number of therapeutic agents currently available to the physician for treatment of hypertensive urgencies.